Diabetic retinopathy (DR) is the most prominent complication of diabetes and the leading cause of blindness in working age individuals1,2. It is characterized by an initial microvascular degeneration followed by a compensatory but pathological hyper-vascularization mounted by the hypoxic retina in an attempt to reinstate metabolic equilibrium3-5. Although often initially asymptomatic, loss of sight is provoked primarily by diabetic macular edema (DME), vitreal hemorrhages and in advanced cases, pre-retinal neovascularization and tractional retinal detachment67. Of these, DME is the main cause of central vision loss in diabetics8, affecting over 25% of patients suffering from diabetes. It is triggered secondary to the deterioration of the blood-retinal barrier (BRB) and the consequent increase in extravasation of fluids and plasma components into the vitreous cavity. Ultimately, the decrease in retinal vascular barrier function leads to vasogenic edema and pathological thickening of the retina.
There are generally 3 stages to diabetic retinopathy: i) non-proliferative retinopathy (NPR); ii) macular edema; and iii) proliferative diabetic retinopathy.
The first stage of diabetic retinopathy, non-proliferative retinopathy or background retinopathy often has no noticeable signs or symptoms, although retinal swelling may be present. This is the stage where the tiny capillaries of the retina become semi-permeable membranes (Later, they will leak fluid and blood.). During the earliest stages, diabetic retinopathy is often asymptomatic. This means that there are no noticeable symptoms-such as pain or vision loss- to the patient, but an eye specialist might find signs of the disease. For example, retinal swelling may be present, which can only be detected through an eye examination.
The second stage of diabetic retinopathy is macular edema. The macula is the part of the retina responsible for sharp, direct vision due to its high density in cones photoreceptors. It is situated at the back of the retina. Macular edema refers to the accumulation of fluid within the retina at the macular area (distinct from the condition where the fluid accumulates under the retina). The pathophysiology depends on the primary cause but usually, the end-point is vascular instability and a breakdown of the blood-retinal barrier, leading to visual impairment.
When the center of the macula begins to swell, vision may become blurry. This middle stage of diabetic retinopathy may overlap the other stages. This is the stage where the blood-retinal barrier is compromised and capillaries in the retina begin to leak fluid, causing swelling and blurred vision.
There are two types of macular edema: focal and diffuse. Focal macular edema occurs when the retinal capillaries develop micro-aneurisms which leak fluid, resulting in several distinct points of leakage. Diffuse macular edema is caused by the dilation of retinal capillaries, creating leakage that is diffused over a general area. The type of macular edema present will determine the kind of diabetic retinopathy treatment. Early detection of macular edema helps ensure the most effective treatment.
As the disease advances, minor visual impairment can occur. Although patients are still able to see, they can be frustrated by blurring and blind spots that inhibit clear vision. These symptoms of diabetic retinopathy are sometimes linked to macular edema, which is the swelling of the part of the eye that controls central vision, known as the macula.
As damaged blood vessels begin to break, blood can leak into the eye. This third stage of diabetic retinopathy, called proliferative diabetic retinopathy (PDR), is characterized by cloudiness and impaired vision. When the retinal capillaries break, they are no longer able to supply the retina with the necessary nutrients. The nutrient-starved retina sends out a chemical signal that prompts the growth of new capillaries. This growth is called neovascularization.
The new blood vessels that form as a result of proliferative diabetic retinopathy cause more damage to the eye. These capillaries are unable to restore nutrients to the retina because they are fragile and weak. They also tend to burst, causing blood and fluid to leak into the eye. The new vessels also exert traction on the surrounding structures and connective tissue, which can eventually detach the retina. Intraocular pressure can also increase as a result of the new capillaries, as they can block the ducts where fluid is drained from the eye. This condition is known as neovascular glaucoma. During proliferative diabetic retinopathy, scar tissue development, retinal detachment, and blindness can occur.
If the disease has progressed into proliferative diabetic retinopathy without the patient receiving any preventative care or medical intervention, retinal detachment and blindness can result. At this time, PDR is the leading cause of new cases of blindness in the United States. Retinal detachment, macular edema, and the breakdown of capillaries in the retina can all prevent normal blood flow through the eye and lead to total vision loss.
Macular edema is not limited to the context of diabetes. Hyperpermeability of blood vessels and leakage of the blood-retinal barrier can occur in a number of circumstances. The most frequent form of macular edema is cystoid macular edema, which is characterized by intraretinal edema contained in honeycomb-like spaces. CME is a common pathological response to a variety of insults (e.g., following intraocular (cataract) surgery, in central and branch retinal vein occlusions, following injury to the eye, in association with choroidal tumors or in various types of vascular retinal diseases or retinal dystrophies). CME is also one of the many conditions that may arise from age-related macular degeneration.
Although significant effort has been invested in elucidating the mechanisms that govern macular edema and in particular destructive pre-retinal neovascularization in DR6,9,10, considerably less is known about the cellular processes that lead to increased retinal vascular permeability. Consequently, the current standards of care present non-negligible side-effects. These include increased cataract formation and a harmful rise in intraocular pressure with intravitreal use of corticosteroid9. Similarly, anti-VEGF (vascular endothelial growth factor) therapies, which in general exhibit respectable safety profiles, may be associated with increased thromboembolic events11, possible neuronal toxicity and geographic atrophy when used for long term regiments12,13. Moreover, the first and most widely used form of treatment is panretinal photocoagulation for either proliferative diabetic retinopathy (PDR) or grid/focal laser for DME. Laser-based photocoagulation approaches destroy hypoxic retinal tissue secreting pro-angiogenic factors and inadvertently lead to reduced visual field or central or paracentral scotomas. These therapeutic limitations highlight the need for novel pharmacological targets and interventions.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.